Targeting GLP-1 receptors now has the FDA’s blessing as a way to treat the fatty liver disease called MASH with Novo Nordisk’s weekly injectable drug Wegovy becoming the second approved treatment for this prevalent metabolic disorder.
In MASH, short for metabolic dysfunction-associated steatohepatitis, the buildup of fat in the liver leads to inflammation and scarring of the organ, which is called fibrosis. The FDA’s late Friday regulatory decision for Wegovy covers the treatment of adults whose MASH has led to moderate-to-severe fibrosis. These patients must not have MASH that has progressed to liver cirrhosis, the most advanced stage of the disease. Like its previous approval in obesity, Wegovy’s MASH approval covers use of the drug alongside diet and exercise.
The active ingredient in Wegovy is semaglutide, a peptide engineered to target and activate GLP-1 receptors in the gut. This approach promotes satiety and delays gastric emptying, helping patients feel full so they eat less. This mechanism of action supported the drug’s initial approval in obesity. The way Wegovy works to treat MASH is not fully understood, but reducing body fat is thought to contribute to liver benefit. Approval of the 2.4 mg dose of Wegovy in MASH is based on interim results from a placebo-controlled Phase 3 clinical trial evaluating 1,197 patients with moderate-to-severe MASH. At week 72, results in 800 trial participants showed 63% achieved MASH resolution and no worsening of fibrosis, a goal achieved by 34% of those in the placebo arm.
The regulatory decision for Wegovy in MASH is an accelerated approval based on the interim results at 72 weeks. That benefit must be confirmed by the ongoing Phase 3 trial. Investigators will look to see whether the inflammation and scarring improvements observed at the interim 72-week mark translate into decreases in death, liver transplants, and other liver-related events measured at 240 weeks.
Wegovy was approved for treating obesity in 2021. Last year, the drug expanded its U.S. and European approvals to include reducing the risk of cardiovascular disease, heart attack, and stroke in adults with obesity or overweight. Across all of Wegovy’s approved uses, Novo Nordisk reported more than 36.8 billion Danish krone (about $5.7 billion) in sales in the first half of this year.
“The FDA’s conditional approval of Wegovy for the treatment of adults with noncirrhotic MASH marks a truly pivotal milestone and a significant step forward for the MASH community and those seeking new options,” Dave Moore, Novo Nordisk’s executive vice president of U.S. Operations said in a prepared statement.
With its latest FDA approval, Wegovy will now compete against Rezdiffra, the Madrigal Pharmaceuticals drug whose accelerated approval last year made it the first MASH drug. The small molecule, formulated as a once-daily pill, works by targeting and activating a receptor in the liver called thyroid hormone receptor beta (THR-beta), mediating metabolic activity in the organ. In Madrigal’s report of second quarter 2025 financial results, the company said Rezdiffra accounted for more than $350 million in revenue in the first half of this year.
In a note sent to investors Saturday, Leerink Partners analyst Thomas Smith said that while his firm believes drugs like Wegovy will find use treating some aspects of MASH, the firm expects drug combinations spanning several drug classes will become the standard of care for this disease. Based on discussions with clinicians, Smith said Leerink expects incretin mimetics, including Wegovy, are likely to be preferred for new MASH patients who have metabolic characteristics of the disease, such as obesity and cardiovascular disease, and who are not currently receiving medication to manage these comorbidities.
Leerink still projects strong market uptake for Rezdiffra, with the Madrigal drug being preferred for patients who are already taking a GLP-1 agonist. The firm notes that about 25% of patients taking Rezdiffra are also currently taking a GLP-1 drug and half of patients have tried a GLP-1 drug in the past.
Another factor is the growing use of Eli Lilly’s tirzepatide, the GLP-1- and GIP receptor-targeting peptide marketed as Mounjaro for type 2 diabetes and as Zepbound for weight management. Smith said it’s unlikely a physician will switch a patient already taking one of these Lilly drugs to Novo Nordisk’s product simply because of its MASH approval. For these patients, Rezdiffra would be the drug of choice added on top of tirzepatide. That said, Lilly is preparing to advance to Phase 3 tests in MASH with tirzepatide and retatrutide, a peptide engineered to go after three targets.
For many years, MASH (formerly known as non-alcoholic steatohepatitis, or NASH) was a tough indication for drug developers. Genfit and Intercept Pharmaceuticals are among the biotechs that encountered clinical trial and regulatory setbacks in the metabolic disease. But Leerink’s Smith says the FDA nod for Wegovy in MASH, with a label consistent with the drug’s clinical trial experience, bolsters confidence in the accelerated approval pathway for this indication. Leerink sees the latest Wegovy approval having positive readthrough to other drugs in late-stage development for MASH.
Akero Therapeutics is currently in Phase 3 testing with efruxifermin, a fusion protein engineered to mimic FGF21, a protein in the body called that regulates energy expenditure and fat metabolization. The biotech has already reported Phase 2 results showing this once-weekly injection met trial goals showing improvement on measures of MASH at 96 weeks. More detailed results were published last week in the journal The Lancet. 89bio is also in Phase 3 testing with pegozafermin, an engineered version of FGF21. Sagimet Biosciences takes a different approach with denifanstat, an oral small molecule inhibitor of fatty acid synthase (FASN).
“Moving forward, we are encouraged with FDA’s label consistency, timely nature of accelerated approvals, and increasingly progressive views on noninvasive tests (NITs) —all of which are transforming the perceived difficulty of the regulatory path, as well as the clinical and commercial MASH landscape,” Smith said.
Photo: Michael Siluk/UCG/Universal Images Group, via Getty Images
